EGFR signaling in colorectal cancer: A clinical perspective

the ONA take:

Colorectal cancer (CRC) is diagnosed in 1.25 million patients worldwide and accounts for more than 600,000 patients deaths every year. Up to half of those patients will develop metastatic disease (mCRC), which has the poorest prognosis. Advances in treatment options have improved overall survival (OS) for these patients to as long as approximately 30 months. In addition, a shift toward more personalized medicine based on a variety of prognostic and predictive biomarkers is changing how this disease is managed.

The epidermal growth factor receptor (EGFR) signaling pathway is believed to play a pivotal role in tumor growth and the progression of various cancers, including CRC. Unlike other cancer types, oncogenic mutations in the EGFR are rare in patients with CRC. In 35% to 50% of patients with CRC, protein overexpression is the principal mechanism of deregulation.

Two classes of EGFR antagonists were developed to treat cancer: monoclonal antibodies (mAbs), which prevent ligand binding to the receptors, and tyrosine kinase inhibitors (TKIs), small molecules that compete for adenosine triphosphate binding to the TK domain of the receptor. Efficacy of TKIs is restricted to patients carrying EGFR mutations; therefore, patients with CRC in whom EGFR mutations are very rarely detected cannot benefit from these drugs. However, promising results have been seen in the treatment of mCRC with mAbs.

In this review, the authors discuss the medical management of mCRC, specifically describing the molecular biology of mCRC, focusing on the EGFR signaling pathway. They also discuss the role of related biomarkers and therapies. Finally, they summarize the evidence regarding anti-EGFR mAbs.

Gastrointestinal Cancer: Targets and Therapy

Abstract: Colorectal cancer (CRC) remains a formidable health burden worldwide, with up to 50% of patients developing metastases during the course of their disease. This group of CRC patients, characterized by the worst prognosis, has been extensively investigated to improve their life expectancy. Main efforts, focused on the epidermal growth-factor receptor (EGFR), which plays a pivotal role in CRC pathogenesis, have led to the development and introduction in clinical practice of specific targeted therapies (ie, monoclonal antibodies). Subsequently, the scientific community has tried to identify molecular predictors of the efficacy of such therapies. However, it has become clear that EGFR alterations occurring in CRC are difficult to investigate, and therefore their predictive role is unclear. In contrast, the clinical role of two downstream members (KRAS and NRAS) has been clearly demonstrated. Currently, EGFR-targeted therapies can be administered only to patients with wild-type KRAS and NRAS genes. Our review addresses the medical management of metastatic CRC. Specifically, we describe in detail the molecular biology of metastatic CRC, focusing on the EGFR signaling pathway, and we discuss the role of current and emerging related biomarkers and therapies in this field. We also summarize the clinical evidence regarding anti-EGFR monoclonal antibodies and examine potential future perspectives.

Introduction

With 1.25 million patients diagnosed with the disease, colorectal cancer (CRC) remains a formidable health burden worldwide, accounting for more than 600,000 patient deaths every year.1,2Approximately a quarter of patients present with synchronous metastases, and up to 50% of patients will develop metastases during the course of their disease.3 As a result of advances over the last 2 decades, overall survival (OS) may now be as long as approximately 30 months in patients with the poorest prognosis, characterized by metastatic disease (mCRC), with up to 70% of these patients receiving at least two treatment lines.4–8 These achievements are attributed to the introduction of new chemotherapeutic agents, the incorporation of novel targeted therapies, and the expansion of indications for liver resection. In parallel, great effort is underway to shift from a “one size fits all” approach to more personalized medicine. Regarding this latter approach, a variety of prognostic (ie, information on the natural history of the patient's disease independent of treatments) and predictive (ie, information concerning the likelihood of response to a particular treatment) biomarkers are under evaluation.

Our review addresses the medical management of mCRC. Specifically, we describe the molecular biology of mCRC, focusing on the epidermal growth factor receptor (EGFR) signaling pathway, and we discuss the role of current and emerging related biomarkers and therapies in this field. We also summarize the clinical evidence regarding anti-EGFR monoclonal antibodies (mAbs) and examine potential future perspectives.